Most new therapeutic measures that protect infarct size in experimental animals have failed in the clinics, to a large extent because they are only effective when administered prior to coronary artery occlusion. Our preliminary data indicate that an adenylyl cyclase type 5 (AC5) inhibitor, vidarabine (also known as Ara-A, AraAde, and Vira-A) appears to reduce infarct size when administered after coronary artery reperfusion (see preliminary data). This drug, which is already FDA approved, as an antiviral compound, will be potentially useful for patients with myocardial infarction (MI), who undergo reperfusion therapy. Even more important, this drug will be useful in the setting of acute coronary syndrome, which is becoming increasingly prevalent1 and despite current advances, the mortality of acute coronary syndrome remains high2. Acute coronary syndrome encompasses a broad spectrum of clinical conditions consistent with acute myocardial infarction (AMI) or angina and accounts for 1.36 million hospitalizations a year. The key feature of acute coronary syndrome is that the patients develop ischemic episodes giving the physician warning of an impending MI, making the use of an agent that reduces infarct size after MI extremely useful, particularly one that is effective following a preceding ischemic event. In phase I we will focus on determining the extent to which AC5 inhibitor protects infarct size when administered either after coronary artery reperfusion following coronary occlusion in a heart virgin to ischemia, in the post ischemic setting after a 15 minute (sentinel) coronary occlusion which induces a small infarct followed by a longer period of test ischemia at 8 hours after the initial ischemic insult, at a time when neithr first nor second window ischemic preconditioning is active, and AC5 inhibitor administration after the prolonged 30 minute ischemic event. Once Aims 1and 2 have been completed, in phase II we propose to test AC5 inhibition for acute coronary syndrome in a pig model for efficacy and safety, and if the results are positive we will move to a clinical trial, since the drg is already FDA approved. PUBLIC HEALTH RELEVANCE: According to the 2009 AHA heart disease and stroke statistics it has been estimated that 1 out of every 5 deaths in the United States is caused by coronary heart disease and myocardial infarction. The current proposal will develop a drug, already FDA approved, that can be given to patients with acute myocardial infarction as well as to those with acute coronary syndrome. Acute coronary syndrome encompasses a broad spectrum of clinical conditions consistent with acute myocardial infarction and accounts for 1.36 million hospitalizations a year.